title: Fc-glycosylation of IgG1 is modulated by B-cell stimuli.
abstract: We have recently shown that IgG1 directed against antigens thought to be involved in the pathogenesis of rheumatoid arthritis harbor different glycan moieties on their Fc-tail, as compared with total sera IgG1. Given the crucial roles of Fc-linked N-glycans for the structure and biological activity of IgG, Fc-glycosylation of antibodies is receiving considerable interest. However, so far little is known about the signals and factors that could influence the composition of these carbohydrate structures on secreted IgG produced by B lymphocytes. Here we show that both "environmental" factors, such as all-trans retinoic acid (a natural metabolite of vitamin A), as well as factors stimulating the innate immune system (i.e. CpG oligodeoxynucleotide, a ligand for toll-like receptor 9) or coming from the adaptive immune system (i.e. interleukin-21, a T-cell derived cytokine) can modulate IgG1 Fc-glycosylation. These factors affect Fc-glycan profiles in different ways. CpG oligodeoxynucleotide and interleukin-21 increase Fc-linked galactosylation and reduce bisecting N-acetylglucosamine levels, whereas all-trans retinoic acid significantly decreases galactosylation and sialylation levels. Moreover, these effects appeared to be stable and specific for secreted IgG1 as no parallel changes of the corresponding glycans in the cellular glycan pool were observed. Interestingly, several other cytokines and molecules known to affect B-cell biology and antibody production did not have an impact on IgG1 Fc-coupled glycan profiles. Together, these data indicate that different stimuli received by B cells during their activation and differentiation can modulate the Fc-linked glycosylation of secreted IgG1 without affecting the general cellular glycosylation machinery. Our study, therefore, furthers our understanding of the regulation of IgG1 glycosylation at the cellular level.
authors.affiliation: Department of Rheumatology, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Crina I A
authors.initials: CI
authors.lastname: Balog
authors.forename: Kathrin
authors.initials: K
authors.lastname: Stavenhagen
authors.forename: Carolien A M
authors.initials: CA
authors.lastname: Koeleman
authors.forename: Hans Ulrich
authors.initials: HU
authors.lastname: Scherer
authors.forename: Maurice H J
authors.initials: MH
authors.lastname: Selman
authors.forename: André M
authors.initials: AM
authors.lastname: Deelder
authors.forename: Tom W J
authors.initials: TW
authors.lastname: Huizinga
authors.forename: René E M
authors.initials: RE
authors.lastname: Toes
authors.forename: Manfred
authors.initials: M
authors.lastname: Wuhrer
mesh_terms: D000117:Acetylglucosamine / Q000378:metabolism; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D002478:Cells, Cultured; D005690:Galactose / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000378:metabolism*; D007378:Interleukins / Q000494:pharmacology; D051379:Mice; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D012794:Sialic Acids / Q000378:metabolism; D013256:Steroids / Q000494:pharmacology; D014212:Tretinoin / Q000031:analogs & derivatives / Q000494:pharmacology; D000098546:Interleukin-21
chemical_list: C408982:CPG-oligonucleotide; D002352:Carrier Proteins; C559105:EA-4 (ATRA steroidal analog); D007141:Immunoglobulin Fc Fragments; D007378:Interleukins; D009838:Oligodeoxyribonucleotides; D012794:Sialic Acids; D013256:Steroids; C029702:prolactin-binding protein; D014212:Tretinoin; D000098546:Interleukin-21; D000117:Acetylglucosamine; D005690:Galactose